Genetic Variant UHMK1:p.Lys265Ile (chr1-162503794-A-T) – ACMG Classification: Uncertain_significance (1 pts)

Variant summary

Our verdict is Uncertain significance. Variant got 1 ACMG points: 2P and 1B. PM2BP4

The NM_175866.5(UHMK1):c.794A>T(p.Lys265Ile) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.00000616 in 1,461,836 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

Frequency

Genomes: not found (cov: 32)

Exomes 𝑓: 0.0000062 ( 0 hom. )

Consequence

UHMK1
NM_175866.5 missense

Scores

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 7.96

Variant links:

Genes affected

UHMK1 (HGNC:19683): (U2AF homology motif kinase 1) The gene encodes a serine/threonine protein kinase that promotes cell cycle progression through G1 by phosphorylation of the cyclin-dependent kinase inhibitor 1B (p27Kip1), which causes nuclear export and degradation. The encoded protein is also thought to function in the adult nervous system and the gene has been associated with schizophrenia. Alternative splicing results in multiple transcript variants. [provided by RefSeq, May 2010]

UHMK1 links:

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ACMG classification

Classification made for transcript

Verdict is Uncertain_significance. Variant got 1 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

BP4

Computational evidence support a benign effect (MetaRNN=0.2810784).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
UHMK1	NM_175866.5 link	c.794A>T	p.Lys265Ile	missense_variant	Exon 4 of 8	ENST00000489294.2	NP_787062.1	Q8TAS1-1
UHMK1	NM_001184763.1 link	c.572A>T	p.Lys191Ile	missense_variant	Exon 4 of 8		NP_001171692.1	Q8TAS1-3
UHMK1	NM_144624.2 link	c.794A>T	p.Lys265Ile	missense_variant	Exon 4 of 7		NP_653225.2	Q8TAS1-2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	UniProt
UHMK1	ENST00000489294.2 link	c.794A>T	p.Lys265Ile	missense_variant	Exon 4 of 8	1	NM_175866.5	ENSP00000420270.1	Q8TAS1-1
UHMK1	ENST00000538489.5 link	c.794A>T	p.Lys265Ile	missense_variant	Exon 4 of 7	1		ENSP00000446416.1	Q8TAS1-2
UHMK1	ENST00000545294.5 link	c.572A>T	p.Lys191Ile	missense_variant	Exon 4 of 8	2		ENSP00000441226.1	Q8TAS1-3
UHMK1	ENST00000282169.8 link	n.1375A>T		non_coding_transcript_exon_variant	Exon 3 of 7	2

Frequencies

GnomAD3 genomes

Cov.:

GnomAD3 exomes

AF:

0.00000796

AC:

AN:

251414

Hom.:

AF XY:

0.00000736

AC XY:

AN XY:

135882

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.00

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad SAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.0000176

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.00000616

AC:

AN:

1461836

Hom.:

Cov.:

AF XY:

0.00000688

AC XY:

AN XY:

727216

show subpopulations

Gnomad4 AFR exome

AF:

0.00

Gnomad4 AMR exome

AF:

0.00

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.00

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.00000809

Gnomad4 OTH exome

AF:

0.00

GnomAD4 genome

Cov.:

Alfa

AF:

0.0000282

Hom.:

Bravo

AF:

0.0000151

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

LINK: link

Submissions by phenotype

not specified

Uncertain:1

Dec 21, 2024

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.794A>T (p.K265I) alteration is located in exon 4 (coding exon 4) of the UHMK1 gene. This alteration results from a A to T substitution at nucleotide position 794, causing the lysine (K) at amino acid position 265 to be replaced by an isoleucine (I). Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear. -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Uncertain

0.51

BayesDel_addAF

Benign

0.011

BayesDel_noAF

Benign

-0.21

CADD

Pathogenic

DANN

Uncertain

0.99

DEOGEN2

Benign

0.18

.;.;T

Eigen

Uncertain

0.53

Eigen_PC

Uncertain

0.63

FATHMM_MKL

Pathogenic

0.99

LIST_S2

Uncertain

0.89

D;D;D

M_CAP

Benign

0.026

MetaRNN

Benign

0.28

T;T;T

MetaSVM

Benign

-0.66

MutationAssessor

Benign

0.85

.;L;L

PrimateAI

Uncertain

0.53

PROVEAN

Benign

-1.1

N;N;N

REVEL

Benign

0.28

Sift

Uncertain

0.0040

D;D;D

Sift4G

Benign

0.13

T;T;T

Polyphen

0.96, 0.92

.;D;P

Vest4

0.43

MVP

0.32

MPC

1.0

ClinPred

0.53

GERP RS

6.1

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.7

Varity_R

0.15

gMVP

0.59

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.010

Details are displayed if max score is > 0.2

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

LitVar

Below is the list of publications found by LitVar. It may be empty.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over